Letter

Nature 446, 815-819 (12 April 2007) | doi:10.1038/nature05697; Received 26 October 2006; Accepted 20 February 2007

Synthetic lethal screen identification of chemosensitizer loci in cancer cells

Angelique W. Whitehurst1, Brian O. Bodemann1, Jessica Cardenas1, Deborah Ferguson2, Luc Girard3, Michael Peyton3, John D. Minna3,4, Carolyn Michnoff5, Weihua Hao5, Michael G. Roth5, Xian-Jin Xie4,6 & Michael A. White1,4

  1. Department of Cell Biology,
  2. Reata Pharmaceuticals,
  3. Hamon Center for Therapeutic Oncology Research,
  4. Simmons Cancer Center,
  5. Department of Biochemistry, and,
  6. Center for Biostatistics and Clinical Science, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA

Correspondence to: Michael A. White1,4 Correspondence and requests for materials should be addressed to M.A.W. (Email: michael.white@utsouthwestern.edu).

Abundant evidence suggests that a unifying principle governing the molecular pathology of cancer is the co-dependent aberrant regulation of core machinery driving proliferation and suppressing apoptosis1. Anomalous proteins engaged in support of this tumorigenic regulatory environment most probably represent optimal intervention targets in a heterogeneous population of cancer cells. The advent of RNA-mediated interference (RNAi)-based functional genomics provides the opportunity to derive unbiased comprehensive collections of validated gene targets supporting critical biological systems outside the framework of preconceived notions of mechanistic relationships. We have combined a high-throughput cell-based one-well/one-gene screening platform with a genome-wide synthetic library of chemically synthesized small interfering RNAs for systematic interrogation of the molecular underpinnings of cancer cell chemoresponsiveness. NCI-H1155, a human non-small-cell lung cancer line, was employed in a paclitaxel-dependent synthetic lethal screen designed to identify gene targets that specifically reduce cell viability in the presence of otherwise sublethal concentrations of paclitaxel. Using a stringent objective statistical algorithm to reduce false discovery rates below 5%, we isolated a panel of 87 genes that represent major focal points of the autonomous response of cancer cells to the abrogation of microtubule dynamics. Here we show that several of these targets sensitize lung cancer cells to paclitaxel concentrations 1,000-fold lower than otherwise required for a significant response, and we identify mechanistic relationships between cancer-associated aberrant gene expression programmes and the basic cellular machinery required for robust mitotic progression.

MORE ARTICLES LIKE THIS

These links to content published by NPG are automatically generated.

REVIEWS

Microtubules and resistance to tubulin-binding agents

Nature Reviews Cancer Review (01 Mar 2010)

Targeted anti-mitotic therapies: can we improve on tubulin agents?

Nature Reviews Cancer Review (01 Feb 2007)

Death through a tragedy: mitotic catastrophe

Cell Death and Differentiation Review

See all 8 matches for Reviews

Extra navigation

.

naturejobs

ADVERTISEMENT